Tetracyclines constitute a family of well known natural and synthetic broad spectrum antibiotics. The parent compound, tetracycline, exhibits the following general structure: ##STR1##
The numbering system of the ring nucleus is as follows: ##STR2##
Tetracycline as well as the 5-OH (Terramycin) and 7-Cl (Aureomycin) derivatives exist in nature, and are well known antibiotics. Natural tetracyclines may be modified without losing their antibiotic properties, although certain elements of the structure must be retained. The modifications that may and may not be made to the basic tetracycline structure have been reviewed by Mitscher in The Chemistry of Tetracyclines, Chapter 6, Marcel Dekker, Publishers, N.Y. (1978). According to Mitscher, the substituents at positions 5-9 of the tetracycline ring system may be modified without the complete loss of antibiotic properties. Changes to the basic ring system or replacement of the substituents at positions 1-4 and 10-12, however, generally lead to synthetic tetracyclines with substantially less or effectively no antibacterial activity. For example, 4-dedimethylaminotetracycline is commonly considered to be a non-antibacterial tetracycline.
The use of tetracycline antibiotics, while effective, may lead to undesirable side effects. For example, the long term administration of antibiotic tetracyclines may reduce or eliminate healthy flora, such as intestinal flora, and may lead to the production of antibiotic resistant organisms or the overgrowth of opportunistic yeast and fungi.
In addition to their antibiotic properties, tetracyclines are also known to inhibit the activity of collagen destructive enzymes such as mammalian collagenase, macrophage elastase and bacterial collagenase; Golub et al., J. Periodont. Res. 20, 12-23 (1985), Golub et al., Crit. Revs. Oral Biol. Med. 2, 297-332 (1991). Collagen is a major component of connective tissue matrices such as those in bone, synovium, eye, skin, tendons and gingiva. Collagenase, which is naturally produced by only a few types of bacteria and in a number of tissues and cells in mammals, degrades collagen.
The degradation of collagen by mammalian collagenase is a natural part of the normal growth-degradation-regeneration process that occurs in connective tissue. The production of collagenase, however, may become excessive. Such excessive collagenase production often results in the pathologic and debilitating destruction of connective tissue.
U.S. Pat. No. 4,704,383 to McNamara et al. discloses that tetracyclines having substantially no effective antibacterial activity inhibit collagenolytic enzyme activity in rats. McNamara et al. also report that non-antibacterial tetracyclines reduce bone resorption in organ culture, although no clinical studies were reported.
Earlier, U.S. Pat. No. 4,666,897 to Golub, et al. disclosed that tetracyclines in general, including commercially-available antimicrobial forms of the drug, inhibit excessive mammalian collagenolytic enzyme activity resulting in decreased connective tissue breakdown including that which occurs during bone resorption.
There have been a number of suggestions that tetracyclines, including non-antibacterial tetracyclines, are effective in treating arthritis in rats. See, for example, Golub et al., "Tetracyclines (TCs) Inhibit Metalloproteinases (MPs): In Vivo Effects In Arthritic And Diabetic Rats, And New In Vitro Studies," abstract presented at Matrix Metallo-proteinase Conference, Destin, Florida, Sep. 11-15, 1989; Breedveld, "Suppression Of Collagen And Adjuvant Arthritis By A Tetracycline," Northeastern Regional Meeting Of The Amer. Rheum. Assoc., Atlantic City, New Jersey, Oct. 23-24, 1987. For a related commentary regarding the effect of non-antibacterial tetracyclines on bone loss see Sipos et al., "The Effect Of Collagenase Inhibitors On Alveolar Bone Loss Due To Periodontal Disease In Desalivated Rats," abstract presented at Matrix Metalloproteinase Conference, Destin, Florida, Sep. 11-15, 1989.
An effect of tetracyclines independent of antibiotic effects has, however, not been established for human patients with rheumatoid arthritis. Thus, Skinner et al., Arthritis and Rheumatism 14, 727-732 (1971), reported no significant benefit from tetracycline therapy for human sufferers of rheumatoid arthritis even though Greenwald et al., reported in J. Rheumatol. 14, 28-32 (1987) that the oral administration of a tetracycline to humans with severe rheumatoid arthritis decreased the collagenase activity in the joint tissues.
It is known that, unlike tetracyclines, non-steroidal anti-inflammatory agents are useful in the symptomatic treatment of rheumatoid arthritis as well as other inflammatory diseases. Such agents, however, do not effectively prevent long term destruction of joint-connective tissues including tendons, cartilage and bone caused by the presence of excessive amounts of collagenase.
Excessive collagenase activity has also been implicated in certain skin disorders. According to White, Lancet, Apr. 29, 1989, p. 966 (1989) the tetracycline, minocycline, is effective in treating dystrophic epidermolysis bullosa, which is a life-threatening skin condition believed to be related to excess collagenase produced in the dermis.
The effectiveness of tetracycline in skin disorders has also been studied by Elewski et al., Journal of the American Academy of Dermatology 8, 807-812 (1983). Elewski et al. disclosed that tetracycline antibiotics may have anti-inflammatory activity in skin and speculate that a portion of the therapeutic effect in skin diseases associated with bacteria, e.g., acne, may be due to inhibition of bacterially induced inflammation rather than a direct antibacterial effect.
Similarly, Plewig et al., Journal of Investigative Dermatology 65, 532-532 (1975), disclose experiments designed to test the hypothesis that antimicrobials are effective in treating inflammatory dermatoses. The experiments of Plewig et al. establish that tetracyclines have anti-inflammatory properties in treating pustules induced by potassium iodide patches.
There has also been speculation that collagenase is involved in bone resorption. For example, Cowen et al., Biochemistry International 11, 273-280 (1985), hypothesize that osteoblast production of collagenase might be an initiating event in bone resorption, leaving minerals to be phagocytosed by osteoclasts.
Further, Delaisse et al., Biochemical and Biophysical Research Communications 133, 483-490 (1985), propose that collagenase plays a critical role in bone resorption. The work of Delaisse et al., shows that inhibition of mammalian collagenase and related tissue metalloproteinases prevent the degradation of bone collagen, thus inhibiting the resorption of explanted mouse bones in tissue culture.
The use of tetracyclines in combination with non-steroidal anti-inflammatory agents has been studied in the treatment of inflammatory skin disorders caused by acne vulgaris. Wong et al., Journal of American Academy of Dermatology 11, 1076-1081 (1984), studied the combination of tetracycline and ibuprofen and found that tetracycline was an effective agent against acne vulgaris while ibuprofen was useful in reducing the resulting inflammation by inhibition of cyclooxygenase. Funt, Journal of the American Academy of Dermatology 13, 524-525 (1985), disclosed similar results by combining the tetracycline minocycline and ibuprofen.
In most of the above studies, the tetracycline was believed to be useful for its antibiotic effect. Therefore, with the exception of the disclosure in the McNamara et al. patent, antibacterial tetracyclines were used despite their undesirable side effects.
Despite the above studies, an effective long term treatment for rheumatoid arthritis and other tissue-destructive conditions associated with excess collagenolytic activity has remained elusive. It is an object of this invention to provide such a treatment. Another object of this invention is to provide such a treatment while avoiding the side effects of antibacterial tetracycline therapies.